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A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia.
2013 Dec;163(5):631-9. doi: 10.1111/bjh.12591. Epub 2013 Oct 10.
Grinfeld J, Gerrard G, Alikian M, Alonso-Dominguez J, Ale S, Valgañon M, Nteliopoulos G, White D, Marin D, Hedgley C, O'Brien S, Clark R, Goldman JM, Milojkovic D, Apperley JF, Foroni L.
Abstract
Approximately one-third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 mRNA levels and single nucleotide polymorphisms (SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base-pair insertion (8(+) allele) at the 3' end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in cis with 8(+) (the 3(-) allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8(+) 8(+) or 8(+) N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8(+) and 3(-) (NN, 18%) showed the best outcomes overall. Thus, while SLC22A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so. © 2013 John Wiley & Sons Ltd.
KEYWORDS:
chronic myeloid leukaemia, drug resistance, prognostic factors, tyrosine kinases